Registration Dossier

Administrative data

Description of key information

Skin Irritation:
An in vivo study according to OECD guideline 404 and in compliance with GLP is available. The results of the study do not warrant classification as a category 2 skin irritant according to CLP. Although prolonged effects for the full 14 day observation period were noted in two animals these consisted of barely perceptible erythema which are considered less severe than prolonged effects leading to classification (i.e. alopecia, hyperkeratosis, hyperplasia and scaling).
Eye Irritation:
An in vivo study according to OECD guideline 405 and in compliance with GLP was conducted. The study showed very slight to well-defined conjunctival irritation, however this was not sufficient to warrant classification.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Between 22 October 1997 and 04 November 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study according to OECD/EU guidelines under GLP conditions.
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Animals for this study were selected from a stock supply of healthy adult rabbits of the New Zealand White strain, obtained from Charles River UK Ltd., Margate, Kent, England.
They were in the weight range of 2. 6 to 3.6 kg and approximately 11 to 16 weeks of age, prior to treatment (Day 1). All rabbits were acclimatised to the experimental environment.
The rabbits were selected without conscious bias for the study. They were housed individually in stainless steel cages with perforated floors in Building R14 Room 5.
A standard laboratory diet STANRAB (P) SQC Rabbit Diet and drinking water were provided ad libitum.
The batch of diet used for the study was analysed for nutrients, contaminants and micro-organisms.
Results of routine physical and chemical examination of drinking water as conducted by the supplier, are made available to Huntingdon Life Sciences Ltd as quarterly summaries.
Animal room temperature was maintained at 13 to 25. 5 °C and relative humidity at 25 - 73%. These environmental parameters were recorded daily. Air exchange was maintained at approximately 19 air changes per hour and lighting was controlled by means of a time switch to give 12 hours of artificial light (0700 - 1900 hours) in each 24 hours period.
Each animal was identified by a numbered aluminium tag placed through the edge of one ear. This number was unique within the Huntingdon Life Sciences Acute Toxicology Department throughout the duration of the study. Each cage was identified by a coloured label displaying the study schedule number, animal number and initials of the Study Director and Home Office licensee.
Type of coverage:
semiocclusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.5.ml amount of the test substance
Duration of treatment / exposure:
4 hours
Observation period:
14 days
Number of animals:
3
Details on study design:
TREATMENT PROCEDURE
Approximately 24 hours prior to application of the test substance, hair was removed with electric clippers from the dorso-lumbar region of each rabbit exposing an area of skin approximately 100 mm x 100 mm.
A 0.5.ml amount of the test substance was applied under a 25 mm by 25 mm gauze pad, to one intact skin site on each animal.
Each treatment site was covered with "Elastoplast" elastic adhesive dressing for four hours. The animals were not restrained during the exposure period and were returned to their cages immediately after treatment.
At the end of the exposure period, the semi-occlusive dressing and gauze pad were removed and the treatment site was washed with warm water (37°C) to remove any residual test substance. The treated area was blotted dry with absorbent paper.
Irritation parameter:
erythema score
Basis:
mean
Remarks:
animal: 2446 Female
Time point:
other: 24, 48 and 72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: score 1 at end of study period
Irritation parameter:
erythema score
Basis:
mean
Remarks:
animal: 2447 Female
Time point:
other: 24, 48 and 72 h
Score:
1.7
Max. score:
4
Reversibility:
fully reversible within: 10 days
Irritation parameter:
erythema score
Basis:
mean
Remarks:
animal: 2448 Female
Time point:
other: 24, 48 and 72 h
Score:
1.7
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: score 1 at end of study period
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal: 2446 Female
Time point:
other: 24, 48 and 72 h
Score:
1.7
Max. score:
4
Reversibility:
fully reversible within: 10 days
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal: 2447 Female
Time point:
other: 24, 48 and 72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 9 days
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal 2448 Female
Time point:
other: 24, 48 and 72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritant / corrosive response data:
Well-defined erythema with slight oedema was seen in all animals. Desquamation of the stratum corneum (characterised by dryness/sloughing) was seen in one rabbit on Days 8 and 9. The dermal reactions gradually ameliorated and had resolved in one rabbit by Day 10. However very slight erythema persisted in the remaining two rabbits at study termination on Day 14.
Other effects:
There were no signs of toxicity or ill health in any rabbit during the observation period.

Table 1                      Dermal reactions

 

Rabbit no. & sex

E = Erythema

O = Oedema

Day

1*

2

3

4

5

6

7

8

9

10

11

12

13

14

2446 Female

E

1

2

2

2

2

2

2

2a

1a

1

1

1

1

1

O

0

2

2

1

2

2

2

2

1

0

0

0

0

0

2447 Female

E

1

1

2

2

2

2

2

2

1

0

 

 

 

 

O

1

1

2

1

2

2

2

2

0

0

 

 

 

 

2448 Female

E

1

1

2

2

2

2

2

2

2

2

2

2

2

1

O

0

1

2

1

2

2

2

1

1

1

1

1

1

0

 

*          Approximately 60 minutes after removal of the dressing

a         Desquamation of the stratum corneum (Characterised by dryness and sloughing)

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
A single semi-occlusive application of Montaverdi to intact rabbit skin for four hours elicited well-defined dermal irritation. Slight dermal reactions were noted in two animals at the end of the 14 day observation period, however these were only minimal in nature and not considered sufficient to classify the substance as category 2 skin irritant or R38.
Executive summary:

A study was performed to assess the skin irritation potential of Montaverdi to the rabbit. The method followed was that described in:

EEC Methods for the determination of toxicity, Annex to Directive 92/69/EEC (OJ No. L383A, 29.12.92), Part B, Method B.4. Acute toxicity (skin irritation) and OECD Guideline for Testing of Chemicals No. 404 "Acute Dermal Irritation/Corrosion". Adopted: 17 July 1992. Three rabbits were each administered a single dermal dose of 0. 5 ml of the test substance and observed for up to 14 days. A single semi-occlusive application of Montaverdi to intact rabbit skin for four hours elicited persistent welldefined dermal irritation. Reactions had resolved in one animal by Day 10 but slight erythema was noted in the remaining two rabbits at study termination on Day 14. The effects seen in 2 of the animals for the 14 day observation period were only minimal in nature and therefore classification as a category 2 irritant is not warranted.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Between 27 October 1997 and 01 November 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted according to OECD/EU guideline under GLP conditions.
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
The values for temperature and humidity were recorded as 13 - 25.5°C and 25 - 73% respectively. These were outside the ranges as stated in the protocol. These deviations are not considered to affect the validity of the study.
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
The values for temperature and humidity were recorded as 13 - 25.5°C and 25 - 73% respectively. These were outside the ranges as stated in the protocol. These deviations are not considered to affect the validity of the study.
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Animals for this study were selected from a stock supply of healthy adult rabbits of the New Zealand White strain, obtained from Charles River UK Ltd., Margate, Kent, England.
The animals were in the weight range of 3.0 to 3.5 kg and approximately 13 to 15 weeks of age, prior to treatment (Day 1). All rabbits were acclimatised to the experimental environment.
The rabbits were selected without conscious bias for the study. They were housed individually in metal cages with perforated floors in Building R14 Room 5.
A standard laboratory diet SDS Stanrab (P) SQC Rabbit Diet and drinking water were provided ad libitum
The batch of diet used for the study was analysed for nutrients, contaminants or micro-organisms.
Results of routine physical and chemical examination of drinking water as conducted by the supplier, are made available to Huntingdon Life Sciences Ltd as quarterly summaries.
Animal room temperature was maintained at l3 to 25.5°C and relative humidity at 25 - 73%. These environmental parameters were recorded daily. Air exchange was maintained at approximately 19 air changes per hour and lighting was controlled by means of a time switch to give 12 hours of artificial light (0700 - 1900 hours) in each 24 hours period.
Each animal was identified by a numbered aluminium tag placed through the edge of one ear. This number was unique within the Huntingdon Life Sciences Acute Toxicology Department throughout the duration of the study. Each cage, was identified by a coloured label displaying the study schedule number, animal number and initials of the Study Director and Home Office licensee.
Vehicle:
unchanged (no vehicle)
Controls:
other: The contralateral eye remained untreated.
Amount / concentration applied:
0.1 ml of the test substance
Duration of treatment / exposure:
Up to 1 hour
Observation period (in vivo):
Examination of the eyes was made after 1 hour and 1, 2, 3 days (equivalent to 24, 48 and 72 hours) after instillation.
Number of animals or in vitro replicates:
3 animals were tested in total. One animal was treated in advance of the others, to ensure that if a severe response was produced, no further animals would be exposed.
Details on study design:
TREATMENT PROCEDURE
The eyes of each animal were examined prior to instillation of the test substance to ensure that there was no pre-existing corneal damage, iridial or conjunctival inflammation.
One animal was treated in advance of the others, to ensure that if a severe response was produced, no further animals would be exposed (pilot animal).
A volume of 0.1 ml of the test substance was placed into the lower everted lid of one eye of each animal.
The eyelid was then gently held together for one second before releasing. The contralateral eye remained untreated.

OBSERVATIONS
Clinical signs
All animals were observed daily for signs of ill health or toxicity.
Ocular responses
Examination of the eyes was made after 1 hour and 1, 2, 3 days (equivalent to 24, 48 and 72 hours) after instillation. Observation of the eyes was aided by the use of a handheld light.
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
animal: 2452 Female
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: No effects observed
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
animal: 2453 Female
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: No effects observed
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
animal: 2454 Female
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: No effects observed
Irritation parameter:
iris score
Basis:
mean
Remarks:
animal: 2452 Female
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: No effects observed
Irritation parameter:
iris score
Basis:
mean
Remarks:
animal: 2453 Female
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: No effects observed
Irritation parameter:
iris score
Basis:
mean
Remarks:
animal: 2454 Female
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: No effects observed
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
animal: 2452 Female
Time point:
other: 24, 48 and 72 hours
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 24 hours
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
animal: 2453 Female
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
animal: 2454 Female
Time point:
other: 24, 48 and 72 hours
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
animal: 2452 Female
Time point:
other: 24, 48 and 72
Score:
0
Max. score:
4
Reversibility:
other: No effects observed
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
animal: 2453 Female
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: no effects observed
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
animal: 2454 Female
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: no effects observed
Irritant / corrosive response data:
No corneal damage or iridial inflammation was observed.
A diffuse crimson colouration of the conjunctivae was seen in two rabbits accompanied by slight swelling of the eyelids. Transient hyperaemia of blood vessels of the conjunctivae was seen in the remaining animal.
All reactions had resolved completely by two or three days after instillation.
Other effects:
There were no signs of toxicity or ill health in any rabbit during the observation period.

Table 1                       Ocular Reactions

 

Rabbit no. and sex

Region of eye

One hour

Day after instillation

1

2

3

2452 Female*

Cornea

Density

0

0

0

0

Area

0

0

0

0

Iris

0

0

0

0

Conjunctiva

Redness

1

1

0

0

Chemosis

0

0

0

0

2453 Female

Cornea

Density

0

0

0

0

Area

0

0

0

0

Iris

0

0

0

0

Conjunctiva

Redness

2

2

1

0

Chemosis

1

0

0

0

2454 Female

Cornea

Density

0

0

0

0

Area

0

0

0

0

Iris

0

0

0

0

Conjunctiva

Redness

2

1

0

0

Chemosis

1

0

0

0

 

* - Pilot animal

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Instillation of 97-204-01 into the rabbit eye elicited transient very slight to well-defined conjunctival irritation but not sufficient to warrant classification.
Executive summary:

An in vivo study was performed to assess the eye irritation potential of Montaverdi to the rabbit. The method followed was that described in:

EEC Methods for the determination of toxicity, Annex to Directive 92/69/EEC (01 No. L383A, 29.12.92), Part B, Method B.5. Acute toxicity (eye irritation) or OECD Guideline for Testing of Chemicals No. 405, "Acute Eye Irritation/Corrosion". Adopted: 24 February 1987. Three rabbits were each administered a single ocular dose of a volume of 0.1 ml of the test substance and observed for three days after instillation. A single instillation of Montaverdi into the eye of the rabbit elicited transient very slight to well-defined conjunctival irritation. The scores obtained however do not lead to classification according to the criteria set out in the DSD 67/548/EC or the CLP Regulation (EC) 1272/2008.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for selection of skin irritation / corrosion endpoint:
This study w as conducted to OECD guidelines and GLP, and can be considered a study that has been conducted according to klimisch reliability 1.

Justification for selection of eye irritation endpoint:
This study w as conducted to OECD guidelines and GLP, and can be considered a study that has been conducted according to a klimisch reliability of 1.

Justification for classification or non-classification

Based on the scores obtained in the skin and eye irritation study, in accordance with the classification criteria set out in the DSD 67/548/EC and the CLP Regulation (EC) 1272/2008 the substance does not need to be classified for skin or eye irritation.